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Nrf2 positively regulates SIKE expression in PM 2.5 -incubated cells. (A) L02 cells were transfected with Nrf2 specific siRNA for 24 h, and then were collected for transfection efficiency determination using western blotting analysis. (B) RTqPCR analysis of HO-1, NQO-1, GCLC and GCLM in L02 cells transfected with siNrf2 for 24 h. (C) Western blot (left panel) and RT-qPCR (right panel) analysis of SIKE in L02 cells with siNrf2 transfection for 24 h. (D) Luciferase reporter analysis with HEK-293 cells that were co-transfected with the indicated reporter plasmids plus siNC or siNrf2 and then left untreated or treated with PM 2.5 (0, 25, 50 or 100 μg/ml) for 24 h. (E) L02 cells were transfected with empty plasmid (EP) of Nrf2 plasmids (Nrf2) for 24 h. Cells were then collected for western blotting analysis to measure Nrf2 expression levels. (F) RT-qPCR analysis of HO-1, NQO-1, GCLC and GCLM in L02 cells transfected with Nrf2 plasmids for 24 h. (G) Western blot (left panel) and RT-qPCR (right panel) analysis of SIKE in L02 cells transfected with 24 h of Nrf2 plasmids. (H) Luciferase reporter analysis with HEK-293 cells transfected with the
Source publication
Air pollution containing particulate matter (PM) less than 2.5 μm (PM2.5) plays an essential role in regulating hepatic disease. However, its molecular mechanism is not yet clear, lacking effective therapeutic strategies. In this study, we attempted to investigate the effects and mechanisms of PM2.5 exposure on hepatic injury by the in vitro and in...
Contexts in source publication
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... Nrf2 was inhibited or over-expressed to further explore its regulatory effect on SIKE and TBK1/NF-κB signaling. As shown in Fig. 2A, Nrf2 was successfully inhibited by transfection with its specific siRNA. As expected, HO-1, NQO-1, GCLC and GCLM expression levels were markedly reduced in L02 cells with Nrf2 knockdown (Fig. 2B). Notably, western blot and RT-qPCR results showed that SIKE protein and mRNA expression levels were greatly decreased in L02 cells ...
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... Nrf2 was inhibited or over-expressed to further explore its regulatory effect on SIKE and TBK1/NF-κB signaling. As shown in Fig. 2A, Nrf2 was successfully inhibited by transfection with its specific siRNA. As expected, HO-1, NQO-1, GCLC and GCLM expression levels were markedly reduced in L02 cells with Nrf2 knockdown (Fig. 2B). Notably, western blot and RT-qPCR results showed that SIKE protein and mRNA expression levels were greatly decreased in L02 cells transfected with siNrf2 (Fig. 2C). HEK-293 cells have been widely used for studying gene function due to its relatively higher transfection efficiency [42]. To further study the relation between SIKE ...
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... was successfully inhibited by transfection with its specific siRNA. As expected, HO-1, NQO-1, GCLC and GCLM expression levels were markedly reduced in L02 cells with Nrf2 knockdown (Fig. 2B). Notably, western blot and RT-qPCR results showed that SIKE protein and mRNA expression levels were greatly decreased in L02 cells transfected with siNrf2 (Fig. 2C). HEK-293 cells have been widely used for studying gene function due to its relatively higher transfection efficiency [42]. To further study the relation between SIKE signaling and Nrf2 activation with greater depth, we transfected HEK-293 cells with luciferase reporter vectors and/or siNrf2, followed by treatment with 0, 25, 50 and 100 ...
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... for studying gene function due to its relatively higher transfection efficiency [42]. To further study the relation between SIKE signaling and Nrf2 activation with greater depth, we transfected HEK-293 cells with luciferase reporter vectors and/or siNrf2, followed by treatment with 0, 25, 50 and 100 μg/ml of PM 2.5 for another 24 h. As shown in Fig. 2D, knockdown of Nrf2 significantly down-regulated SIKE, while promoted p-TBK1 and p-NF-κB activation reporter gene expression, compared with normal cells. Then, Nrf2 was over-expressed in L02 cells by transfection with its specific plasmids, which were along with greatly increased expression of HO-1, NQO-1, GCLC and GCLM ( Fig. 2E and ...
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... 24 h. As shown in Fig. 2D, knockdown of Nrf2 significantly down-regulated SIKE, while promoted p-TBK1 and p-NF-κB activation reporter gene expression, compared with normal cells. Then, Nrf2 was over-expressed in L02 cells by transfection with its specific plasmids, which were along with greatly increased expression of HO-1, NQO-1, GCLC and GCLM ( Fig. 2E and F). Of note, SIKE expression both from protein and mRNA levels were highly elevated in L02 cells with Nrf2 over-expression (Fig. 2G). Luciferase reporter analysis also demonstrated that Nrf2 over-expression abrogated the regulatory effects of PM 2.5 on SIKE, p-TBK1 and p-NF-κB activation in HEK-293 cells (Fig. ...
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... expression, compared with normal cells. Then, Nrf2 was over-expressed in L02 cells by transfection with its specific plasmids, which were along with greatly increased expression of HO-1, NQO-1, GCLC and GCLM ( Fig. 2E and F). Of note, SIKE expression both from protein and mRNA levels were highly elevated in L02 cells with Nrf2 over-expression (Fig. 2G). Luciferase reporter analysis also demonstrated that Nrf2 over-expression abrogated the regulatory effects of PM 2.5 on SIKE, p-TBK1 and p-NF-κB activation in HEK-293 cells (Fig. ...
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... HO-1, NQO-1, GCLC and GCLM ( Fig. 2E and F). Of note, SIKE expression both from protein and mRNA levels were highly elevated in L02 cells with Nrf2 over-expression (Fig. 2G). Luciferase reporter analysis also demonstrated that Nrf2 over-expression abrogated the regulatory effects of PM 2.5 on SIKE, p-TBK1 and p-NF-κB activation in HEK-293 cells (Fig. ...
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... above demonstrated that Nrf2 might positively regulate SIKE expression, whereas inhibit TBK1 and NF-κB activation. Immunofluorescence staining further confirmed that PM 2.5 stimulation obviously reduced Nrf2 and SIKE expression levels, as evidenced by the weaker fluorescence (Fig. 2I). Furthermore, ChIP assay detected the binding of Nrf2 on the SIKE promoter region in L02 cells with or without PM 2.5 exposure (Fig. 2J). Subsequently, western blot analysis confirmed that Nrf2 knockdown markedly reduced SIKE expression under normal condition. PM 2.5 -induced increases in p-TBK1 and p-NF-κB were significantly further ...
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... whereas inhibit TBK1 and NF-κB activation. Immunofluorescence staining further confirmed that PM 2.5 stimulation obviously reduced Nrf2 and SIKE expression levels, as evidenced by the weaker fluorescence (Fig. 2I). Furthermore, ChIP assay detected the binding of Nrf2 on the SIKE promoter region in L02 cells with or without PM 2.5 exposure (Fig. 2J). Subsequently, western blot analysis confirmed that Nrf2 knockdown markedly reduced SIKE expression under normal condition. PM 2.5 -induced increases in p-TBK1 and p-NF-κB were significantly further elevated by Nrf2 knockdown (Fig. 2K). In contrast, SIKE expression was up-regulated when Nrf2 was over-expressed in L02 cells in the ...
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... ChIP assay detected the binding of Nrf2 on the SIKE promoter region in L02 cells with or without PM 2.5 exposure (Fig. 2J). Subsequently, western blot analysis confirmed that Nrf2 knockdown markedly reduced SIKE expression under normal condition. PM 2.5 -induced increases in p-TBK1 and p-NF-κB were significantly further elevated by Nrf2 knockdown (Fig. 2K). In contrast, SIKE expression was up-regulated when Nrf2 was over-expressed in L02 cells in the absence of PM 2.5 . In response to PM 2.5 , promoting Nrf2 could greatly rescued SIKE expression in L02 cells, whereas effectively down-regulated p-TBK1 and p-NF-κB (Fig. 2L). Therefore, results above indicated that Nrf2 might positively ...
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... in p-TBK1 and p-NF-κB were significantly further elevated by Nrf2 knockdown (Fig. 2K). In contrast, SIKE expression was up-regulated when Nrf2 was over-expressed in L02 cells in the absence of PM 2.5 . In response to PM 2.5 , promoting Nrf2 could greatly rescued SIKE expression in L02 cells, whereas effectively down-regulated p-TBK1 and p-NF-κB (Fig. 2L). Therefore, results above indicated that Nrf2 might positively regulate SIKE, contributing to the blockage of TBK1 and ...
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... SIKE-regulated inflammatory response requires TBK1 blockage in PM 2.5 -treated cells To further explore if SIKE-regulated inflammatory response was TBK1-dependent, we constructed adenoviral vectors to knock down TBK1 (Ad-shTBK1) or overexpress TBK1 (Ad-TBK1) in L02 cells (Supplementary fig. 2). Under basal conditions, alterations in either SIKE or TBK1 expression had no significant effect on the expression of inflammatory factors. When L02 cells were exposed to PM 2.5 , however, co-infection with Ad-TBK1 counteracted Ad-SIKE-reduced expression of IL-1β, IL-6, TNF-α and IFN-β, as well as p-NF-κB ( Fig. 4A and B). Conversely, ...
Citations
... Notably, MT afforded anti-oxidative and antiapoptosis efficacy, effectively rescuing bronchial epithelial cells from the damage induced by PM exposure in both mammalian cells and animals. Cumulative evidence supports a role for oxidative stress as a critical pathway in response to PM exposure (Yue et al. 2019;Ge et al. 2020;He et al. 2017). Endogenous ROS is generated from diverse sources, including mitochondrial respiratory chain, NADPH oxidases, nitric oxide synthases, and cytochrome P450 (Nathan and Cunningham-Bussel 2013;Wende et al. 2016). ...
To investigate the mechanism underlying particulate matter (PM) exposure-induced oxidative stress and potential rescue strategies against pulmonary damage in this context.
A combination of omics technology and bioinformatic analysis were used to uncover mechanisms underlying cellular responses to PM exposure in human bronchial epithelia (HBE) cells and imply the potential rescue.
Our results implicated that oxidative stress, metal ion homeostasis, and apoptosis were the major cellular responses to PM exposure in HBE cells. PM exposure disrupted oxidative phosphorylation (OXPHOS)-related gene expressions in HBE cells. Rescuing the expression of these genes with supplemental coenzyme Q10 (Co Q10) inhibited reactive oxygen species (ROS) generation; however, it only partially protected HBEs against PM exposure-induced apoptosis. Further, metallothionein (MT)-encoding genes associated with metal ion homeostasis were significantly induced in HBE cells, which was transcriptionally regulated by specificity protein 1 (SP1). SP1 knock-down (KD) aggravated PM-induced apoptosis in HBE cells, suggesting it plays a role in MT induction. Subsequent studies corroborated the protective role of MT by showing that exogenous MT supplement demonstrated effective protection against PM-induced oxidative stress and apoptosis in HBE cells. Importantly, exogenous MT supplement was shown to reduce ROS generation and apoptosis in airway epithelia in both HBE cells and a PM-inhaled murine model.
This study demonstrates that the impact of MT on airway epithelia by suppressing oxidative stress and maintaining metal ion homeostasis is beneficial in attenuating damage to pulmonary cells undergoing PM exposure.
... Among these, the liver, as the largest digestive gland and a central hub for metabolic activities in the human body, is significantly impacted. Exposure to a PM2.5 environment has been confirmed by numerous in vivo and in vitro experiments to induce the occurrence and development of metabolic-associated fatty liver disease (Ge et al., 2020;Xu et al., 2019). ...
Background
The standardized extract of milk thistle seeds, known as silibinin, has been utilized in herbal medicine for over two centuries, with the aim of safeguarding the liver against the deleterious effects of various toxic substances. However, the role of silibinin in Particulate Matter (PM2.5)-induced intrahepatic triglyceride accumulation remains unclear. This study seeks to investigate the impact of silibinin on PM2.5-induced intrahepatic triglyceride accumulation and elucidate potential underlying mechanisms.
Methods
A model of intrahepatic triglyceride accumulation was established in male C57BL/6J mice through intratracheal instillation of PM2.5, followed by assessment of liver weight, body weight, liver index, and measurements of intrahepatic triglycerides and cholesterol after treatment with silibinin capsules. Hep G2 cells were exposed to PM2.5 suspension to create an intracellular triglyceride accumulation model, and after treatment with silibinin, cell viability, intracellular triglycerides and cholesterol, fluorescence staining for Nile Red (lipid droplets), and DCFH-DA (Reactive Oxygen Species, ROS), as well as proteomics, real-time PCR, and mitochondrial function assays, were performed to investigate the mechanisms involved in reducing triglycerides.
Results
PM2.5 exposure leads to triglyceride accumulation, increased ROS production, elevated expression of inflammatory factors, decreased expression of antioxidant factors, and increased expression of downstream genes of aryl hydrocarbon receptor. Silibinin can partially or fully reverse these factors, thereby protecting cells and animal livers from PM2.5-induced damage. In vitro studies show that silibinin exerts its protective effects by preserving oxidative phosphorylation of mitochondrial complexes I and II, particularly significantly enhancing the function of mitochondrial complex II. Succinate dehydrogenase (mitochondrial complex II) is a direct target of silibinin, but silibinin A and B exhibit different affinities for different subunits of complex II.
Conclusion
Silibinin improved the accumulation of intrahepatic triglycerides induced by PM2.5, and this was, at least in part, explained by an enhancement of oxidative phosphorylation in mitochondrial Complexes I and II.
... As Juglanin is a plant product with anti-inflammatory and anti-oxidative properties, the therapeutic efficacy of Juglanin on PM2.5-induced inflammation, oxidative stress, and liver injury has been assessed [67]. Interestingly, Juglanin (40mg/kg/day, via gavage 6h prior to PM2.5 exposure) reduces PM2.5 (151.1 +/-2.5 µg/m^3, 6 h /day, 5 times/week for 24 weeks)-induced liver injury in mice through activation of antioxidant gene regulator Nrf2, and suppressor of IKKe (SIKE), a known negative regulator of inflammatory signaling. ...
... It is important to note that Nrf2 and SIKE KO mice are more susceptible to PM2.5-induced oxidative stress/ROS generation as shown by higher level of MDA, lower level of SOD, and increased inflammation as shown by higher IL-1, IL-6, TNF-, and liver injury as shown by higher ALT and AST compared to wildtype mice. These in vivo observations on the beneficial effects of Juglanin on PM2.5-induced liver injury have also been replicated in vitro using human liver cell line LO2 [67]. Together, this study suggests the significant involvement of Nrf2 and SIKE pathways in PM2.5-induced liver injury and most importantly, Juglanin is a potential therapeutic agent to controlling PM2.5-induced inflammation, oxidative stress, and liver pathologies. ...
Today, air pollution is one of the greatest threats to organismal healthspan. The environmental air of earth is contaminated with a wide variety of artificially generated pollutants like fine particulate matter (PM2.5) emitting from industry, fuel engine vehicles, biomass combustion, fumes from blasting, crop residue burning, and wildfire. The air pollutant PM2.5 induces massive oxidative stress and inflammation, the major contributors in initiation and progression of numerous diseases including pulmonary, cardiovascular, renal, hepatic, reproductive, neurological, mental, and accelerated biological aging. The provocative question is the following: how can we solve this air pollution associated problem? As it is not realistic to clean the environment at once from artificially generated toxic pollution, initiatives have been undertaken to develop novel therapeutic approaches to control air-pollutant-induced oxidative stress and inflammation and associated devastating diseases. The primary goal of this review article is to discuss systematically the key findings of numerous recent preclinical studies documenting first, the role of air pollutant PM2.5 in augmentation of inflammation, oxidative stress, and associated diseases; and second, the efficacies of different natural and synthetic compounds in amelioration of PM2.5-induced oxidative stress, inflammation, pyroptosis, and associated pathologies. Further investigation on the safety of these compounds will be helpful to select effective and non-toxic compound(s) for clinical trial and drug development.
... As Juglanin is a plant product with anti-inflammatory and anti-oxidative properties, the therapeutic efficacy of Juglanin on PM2.5-induced inflammation, oxidative stress, and liver injury has been assessed [67]. Interestingly, Juglanin (40mg/kg/day, via gavage 6h prior to PM2.5 exposure) reduces PM2.5 (151.1 +/-2.5 µg/m^3, 6 h /day, 5 times/week for 24 weeks)-induced liver injury through activation of antioxidant gene regulator Nrf2, and suppressor of IKKe (SIKE), a known negative regulator of inflammatory signaling. ...
... It is important to note that Nrf2 and SIKE KO mice are more susceptible to PM2.5-induced oxidative stress/ROS generation as shown by higher level of MDA, lower level of SOD, and increased inflammation as shown by higher IL-1 , IL-6, TNF-, and liver injury as shown by higher ALT and AST compared to wildtype mice. These in vivo observations on the beneficial effects of Juglanin on PM2.5-induced liver injury have also been replicated in vitro using human liver cell line LO2 [67]. Together, this study suggests the significant involvement of Nrf2 and SIKE pathways in PM2.5-induced liver injury and most importantly, Juglanin is a potential therapeutic agent to controlling PM2.5-induced inflammation, oxidative stress, and liver pathologies. ...
Today, air pollution is the greatest threat to organismal healthspan. The environment of our planet earth, the habitat of over eight billion humans and estimated twenty billion billions other animals, is contaminated with a wide variety of pollutants. Unfortunately, humans, out of billions and billions of living organisms on earth, are solely responsible for polluting the environment through emitting pollutants like particulate matter from industry, fuel engine vehicles, biomass combustion, toxic fumes from blasting, and wildfire. In the modern world, human-caused air pollutants induce massive oxidative stress and inflammation, the major contributors in initiation and progression of many diseases including pulmonary, cardiovascular, renal, hepatic, reproductive, neurological, mental, and accelerated biological aging. The provocative question is the following: how can we solve this human-created problem? As it is not realistic to clean the environment at once from human-caused pollution, initiatives have been undertaken to develop novel therapeutic approaches to control air-pollutant-induced oxidative stress and inflammation to protect humans from pollution-induced devastating diseases. In this article, I discuss the key findings of numerous recent preclinical studies documenting first, the role of air pollutant PM2.5 in augmentation of inflammation, oxidative stress, and associated diseases; and second, the efficacies of different natural and synthetic compounds in amelioration of PM2.5-induced oxidative stress, inflammation, pyroptosis, and associated pathologies.
... During the later exposure to CFA, the robust immune response tended to be subsided as evidenced by the gradually decreased arthritic score after day 21 (Fig. 2b), the anti-inflammatory property of epalrestat was dominant, and thus suppressed the transcription of inflammatory cytokines, which was consistent with our in vitro data (Fig. 1g). Recently, juglanin, a natural product with partly AR inhibitory [73] and antioxidant activities [74], has been reported to alleviate arthritic phenotype in AIA rats through inactivation of NF-κB and decrease of oxidative stress [75]. Surprisingly, epalrestat with the specific ARI activity leads to more severe arthritic symptoms but co-treatment with NAC, exhibits anti-arthritic and -inflammatory effects in AIA rats. ...
Epalrestat, an aldose reductase inhibitor (ARI), has been clinically adopted in treating diabetic neuropathy in China and Japan. Apart from the involvement in diabetic complications, AR has been implicated in inflammation. Here, we seek to investigate the feasibility of clinically approved ARI, epalrestat, for the treatment of rheumatoid arthritis (RA).
The mRNA level of AR was markedly upregulated in the peripheral blood mononuclear cells (PBMCs) of RA patients when compared to those of healthy donors. Besides, the disease activity of RA patients is positively correlated with AR expression. Epalrestat significantly suppressed lipopolysaccharide (LPS) induced TNF-α, IL-1β, and IL-6 in the human RA fibroblast-like synoviocytes (RAFLSs). Unexpectedly, epalrestat treatment alone markedly exaggerated the disease severity in adjuvant induced arthritic (AIA) rats with elevated Th17 cell proportion and increased inflammatory markers, probably resulting from the increased levels of 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA). Interestingly, the combined treatment of epalrestat with N-Acetylcysteine (NAC), an anti-oxidant, to AIA rats dramatically suppressed the production of 4-HNE, MDA and inflammatory cytokines, and significantly improved the arthritic condition.
Taken together, the anti-arthritic effect of epalrestat was diminished or even overridden by the excessive accumulation of toxic 4-HNE or other reactive aldehydes in AIA rats due to AR inhibition. Co-treatment with NAC significantly reversed epalrestat-induced upregulation of 4-HNE level and potentiated the anti-arthritic effect of epalrestat, suggesting that the combined therapy of epalrestat with NAC may sever as a potential approach in treating RA. Importantly, it could be regarded as a safe intervention for RA patients who need epalrestat for the treatment of diabetic complications.
... The excessive production of ROS can lead to oxidative stress and cause lung injury after PM2.5 exposure . The transcription factor, nuclear factor, erythroid 2 like 2 (NRF2/Nrf2) is the most important regulator of the cellular antioxidant response, regulating the expression of genes that maintain redox homeostasis and electrophilic stresses (Zhao et al., 2022) (Ge et al., 2020). Moreover, many Nrf2 target genes appear to prevent the progression of the ferroptosis cascade (Shin et al., 2018). ...
Background and Purpose
Our previous research showed that ferroptosis plays a crucial role in the pathophysiology of PM2.5‐induced lung injury. The present study aimed to investigate the protective role of the Nrf2 signalling pathway and its bioactive molecule tectoridin in PM2.5‐induced lung injury by regulating ferroptosis.
Experimental Approach
We examined the regulatory effect of Nrf2 on ferroptosis in PM2.5‐induced lung injury and Beas‐2b cells using Nrf2‐knockout (KO) mice and Nrf2 siRNA transfection. The effects and underlying mechanisms of tectoridin on PM2.5‐induced lung injury were evaluated in vitro and in vivo.
Key Results
Nrf2 deletion increased iron accumulation and ferroptosis‐related protein expression in vivo and vitro, further exacerbating lung injury and cell death in response to PM2.5 exposure. Tectoridin activated Nrf2 target genes and ameliorated cell death caused by PM2.5. In addition, tectoridin prevented lipid peroxidation, iron accumulation and ferroptosis in vitro, but in siNrf2‐treated cells, these effects almost disappeared. In addition, tectoridin effectively mitigated PM2.5‐induced respiratory system damage, as evaluated by HE, PAS, and inflammatory factors. Tectoridin also augmented the antioxidative Nrf2 signalling pathway and prevented changes in ferroptosis‐related morphological and biochemical indicators, including MDA levels, GSH depletion and GPX4 and xCT downregulation, in PM2.5‐induced lung injury. However, the effects of tectoridin on ferroptosis and respiratory injury were almost abolished in Nrf2‐KO mice.
Conclusion and Implications
Our data proposed the protective effect of Nrf2 activation on PM2.5‐induced lung injury by inhibiting ferroptosis‐mediated lipid peroxidation and highlight the potential of tectoridin as a PM2.5‐induced lung injury treatment.
... After entering the body, PM2.5 travels to the liver via blood circulation, resulting in liver damage of various degrees 7 . Humans' or animals' exposure to PM2.5 in the environment can cause inflammatory damage and extensive oxidative damage to various organs and tissues including the liver 8 . According to research, once PM2.5 particles enter the body through the lungs, they will adhere to lung tissues and interact with lung epithelial cells as well as lung macrophages, generating and releasing a great amount of cytokines and reactive oxygen species (ROS) 9 . ...
Objective:
The aim of this study was to evaluate the impact of particulate matter 2.5 (PM2.5) on liver function at the animal level and to study its impact targets.
Materials and methods:
60 male and female BALB/c mice of SPF grade, aged 6-8 weeks, were randomly divided into four groups, with 15 mice in each, including the normal saline control group, the PM2.5 low dose group [2 μg/(100 g/d)], the PM2.5 medium dose group [8 μg/(100 g/d)] and the PM2.5 high dose group [16 μg/(100 g/d)]. Each day, 0.9% saline or PM2.5 particles were administered through the nasal route, and samples were taken after 3 weeks of continuous exposure. Hematoxylin-eosin staining (HE) was used to observe the liver damage caused by PM2.5. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were detected by using an automatic biochemical analyzer to detect the content of liver glycogen and blood glucose. Multiple indicators were observed, including plasma tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) levels, oxidative stress response indicators reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) detection, RT-PCR and Western blot detection of glycogen synthase (GS), glucokinase (GK), nuclear factor erythroid 2-related factor 2 (Nrf2) expression and phosphorylation level of phospho-c-Jun N-terminal kinases (p-JNK).
Results:
PM2.5 can cause damage to the liver by increasing PM2.5 concentrations, raising the metabolic rate of liver cells, resulting in a substantial amount of inflammatory infiltration and vacuolar degeneration of cells, and increasing the liver/body weight. TNF-α and IL-6 inflammatory factor expression increased (p<0.05). An increase in the serum ALT and AST levels were also observed. The blood glucose of mice increased, whereas the content of liver glycogen declined (p<0.05). ROS, MDA, and SOD levels all increased considerably. PM2.5 can drastically lower the expression of GS and GK, increase the expression of Nrf2, and raise the phosphorylation level of p-JNK (p<0.05).
Conclusions:
PM2.5 can induce oxidative stress in mouse liver through the Nrf2/JNK pathway, induce liver inflammation in mice, and inhibit glycogen synthesis.
... Notably, MTs afforded anti-oxidative and anti-apoptosis efficacy, effectively rescuing bronchial epithelial cells from the damage induced by PM exposure in both mammalian cells and animals. Cumulative evidence supports a role for oxidative stress as a critical pathway in response to PM exposure (Yue et al. 2019;Ge et al. 2020;He et al. 2017). Endogenous ROS is generated from diverse sources, including mitochondrial respiratory chain, NADPH oxidases, nitric oxide synthases, and cytochrome P450 (Nathan and Cunningham-Bussel 2013;Wende et al. 2016). ...
Purpose
To investigate the mechanism underlying particulate matter (PM) exposure-induced oxidative stress and potential rescue strategies against pulmonary damage in this context.
Methods
A combination of omics technology and bioinformatic analysis were used to uncover mechanisms underlying cellular responses to PM exposure in human bronchial epithelia (HBE) cells and imply the potential rescue.
Results
Our results implicated that oxidative stress, metal ion homeostasis, and apoptosis were the major cellular responses to PM exposure in HBE cells. PM exposure disrupted oxidative phosphorylation (OXPHOS)-related gene expressions in HBE cells. Rescuing the expression of these genes with supplemental coenzyme Q10 (Co Q10) inhibited reactive oxygen species (ROS) generation; however, it only partially protected HBEs against PM exposure-induced apoptosis. Further, metallothionein (MT)-encoding genes associated with metal ion homeostasis were significantly induced in HBE cells, which was transcriptionally regulated by specificity protein 1 (SP1). SP1 knock-down (KD) aggravated PM-induced apoptosis in HBE cells, suggesting it plays a role in MT induction. Subsequent studies corroborated the protective role of MT by showing that exogenous MTs supplement demonstrated effective protection against PM-induced oxidative stress and apoptosis in HBE cells. Importantly, exogenous MTs supplement was shown to reduce ROS generation and apoptosis in airway epithelia in both HBE cells and a PM-inhaled murine model.
Conclusion
This study demonstrates that the impact of MTs on airway epithelia by suppressing oxidative stress and maintaining metal ion homeostasis is beneficial in attenuating damage to pulmonary cells undergoing PM exposure.
... Amyloids can accumulate not only in brain but also in different tissues and body organs that result in clinical syndromes [17]. Studies have shown that exposure to ultrafine PM particles led to influx of inflammatory cytokines in serum, heart, liver and lung of mice [18][19][20][21]. Our recent study has shown that exposure to ambient PM particles resulted in inflammation, deposition of Aβ amyloids and formation of neurofibrillary tangles and plaques in mouse brain [4]. ...
While it is known that air borne ultrafine particulate matter (PM) may pass through the pulmonary circulation of blood at the alveolar level between lung and heart and cross the air-blood barrier, the mechanism and effects are not completely clear. In this study the imaging method fluorescence lifetime imaging microscopy is adopted for visualization with high spatial resolution and quantification of ultrafine PM particles in mouse lung and heart tissues. The results showed that the median numbers of particles in lung of mice exposed to ultrafine particulate matter of diameter less than 2.5 µm was about 2.0 times more than that in the filtered air (FA)-treated mice, and about 1.3 times more in heart of ultrafine PM-treated mice than in FA-treated mice. Interestingly, ultrafine PM particles were more abundant in heart than lung, likely due to how ultrafine PM particles are cleared by phagocytosis and transport via circulation from lungs. Moreover, heart tissues showed inflammation and amyloid deposition. The component analysis of concentrated airborne ultrafine PM particles suggested traffic exhausts and industrial emissions as predominant sources. Our results suggest association of ultrafine PM exposure to chronic lung and heart tissue injuries. The current study supports the contention that industrial air pollution is one of the causative factors for rising levels of chronic pulmonary and cardiac diseases.
... The accumulation of free fatty acid flux in hepatic cells further triggers a "second hit" involving oxidative stress and lipid peroxidation [9]. It has also been reported that PM 2.5 exposure induces excessive oxygen species (ROS) production and redox homeostasis disorder [10,11]. In brief, oxidative stress appears to be an integral mechanism that conveys hepatic injury in MAFLD and plays a well-described role in mediating the toxicity of PM 2.5 [12]. ...
... However, with increasing exposure dose, PM 2.5 inhibits the Nrf2 pathway. Similarly, it has been found that low concentrations of PM 2.5 slightly upregulate Nrf2 expression, and subsequently, PM 2.5 treatment dose-dependently decreases Nrf2 expression [10]. These studies have shown that PM 2.5 induces ROS production and changes in antioxidant genes, which play vital regulatory roles in the progression of MAFLD. ...
Background:
Exposure to fine particulate matter (PM2.5) is associated with the risk of developing metabolic-associated fatty liver disease (MAFLD). Melatonin is the main secreted product of the pineal gland and has been reported to prevent hepatic lipid metabolism disorders. However, it remains uncertain whether melatonin could protect against PM2.5-induced MAFLD.
Methods and results:
The purpose of our study was to investigate the mitigating effects of melatonin on hepatic fatty degeneration accelerated by PM2.5 in vivo and in vitro. Histopathological analysis and ultrastructural images showed that PM2.5 induced hepatic steatosis and lipid vacuolation in ApoE-/- mice, which could be effectively alleviated by melatonin administration. Increased ROS production and decreased expression of antioxidant enzymes were detected in the PM2.5-treated group, whereas melatonin showed recovery effects after PM2.5-induced oxidative damage in both the liver and L02 cells. Further investigation revealed that PM2.5 induced oxidative stress to activate PTP1B, which in turn had a positive feedback regulation effect on ROS release. When a PTP1B inhibitor or melatonin was administered, SP1/SREBP-1 signalling was effectively suppressed, while Nrf2/Keap1 signalling was activated in the PM2.5-treated groups.
Conclusion:
Our study is the first to show that melatonin alleviates the disturbance of PM2.5-triggered hepatic steatosis and liver damage by regulating the ROS-mediated PTP1B and Nrf2 signalling pathways in ApoE-/- mice. These results suggest that melatonin administration might be a prospective therapy for the prevention and treatment of MAFLD associated with air pollution.
